Process for preparing in a selective man-



United States Patent "'ice PROCESS FOR PREPARING IN A SELECTIVE MAN NER MONO- AND DI-ACYL DERIVATIVES F 1-p.NI'I'ROPHENYL-2-AMINO-1,3-PROPANEDIOI S Alberto Vercellone and Carlo Giuseppe Alberta, Milan,

Italy, assignors to Farmaceutici Italia S. A., a corporation of Italy No Drawing. Application August 29, 1951, Serial No. 244,275

Claims priority, application Italy May 30, 1951 7 Claims. (Cl. 260-490) As is known, 1-p.nitrophenyl-2-amino-1,3-propanediols have three functional groups adapted to be acylated; therefore, the importance is evident of finding a method enabling to obtain in a selective manner only the respective monoor di-acyl derivatives, which ofier particular interest for the synthesis of chloramphenicol.

Applicants have in fact already claimed the preparation of said monoand di-acyl derivatives by means of a selective acylation of 1-phenyl-2-arnino-1,3-propanediols, followed by the nitration of the compounds obtained and by the subsequent migration of an acyl group from O to N (applicants copending applications, Serial Nos. 244,273 and 244,274, filed August 29, 1951).

It has now been found that the aforesaid operations of acylation in a selective manner and migration of an acyl group from O to N, optionally with contemporaneous partial saponification, are applicable also to already nitrated starting products, that is to say to 1-p.nitrophenyl-Z-amino-1,3-propanediols.

It is therefore the object of the present invention to provide a process for preparing selectively monoand diacyl derivatives of 1-p.nitrophenyl-2-amino-1,3-propanediols, in particular N-monoacyland N,O-diacyl derivatives, which is essentially characterized by the fact that 1-p.nitrophenyl-2-amino-l,3-propanediols are treated with the chloride of an acid dissolved in the corresponding acid, saturated with hydrochloric acid, and that the 0,0-diacylic hydrochlorides thus obtained are subjected to the simple migration of an acyl group to N, to obtain the N,O-diacyl derivatives, or to said migration with contemporaneous saponification of the other acyl group, to obtain the N-monoacyl derivatives.

In particular, according to the present invention, acylation is carried out at a temperature lower than 40 (1., operating under anhydrous conditions, While the 0,0- diacylic hydrochlorides thus obtained, and separated if so desired, are alkalized, after previous addition of water, to pH lower than 8 to obtain the N,O-diacyl derivatives, or to pH higher than 8, after previously diluting the watery mixture with an organic solvent miscible with water, such as an alcohol, an aliphatic ketone or a cyclic Patented Dec. 13, 1955 As is known, nitrophenylaminopropanediols, as they contain two asymmetric adjacent carbon atoms, can exist in the following six forms; erythro (or regular or cis), threo (pr pseudo 0) or trans), and for each of these in the dextrorotatory, laevorotatory and racenu'c forms; it is understood, therefore, that in the present specification and appended claims, where not otherwise indicated, any of said forms is referred to.

The following examples of the invention are given by way of illustration without limitation.

Example 1 g. of threo-l-p.nitrophenyl-2-amino-1,3-propanediol are dissolved in cc. of glacial acetic acid, and cc. of saturated solution of hydrochloric acid in glacial acetic acid (about 8.5 and 15 cc. of acetyl chloride are added. After one night, dilution is elfected with ether, and threo-1-p.nitrophenyl-1,3-diacetoxy-2-aminopropanc hydrochloride M. P. l59161 C is obtained.

15 g. of said hydrochloride are dissolved in 60 cc. of water and alkalization is effected with 5 g. of sodium bicarbonate. At first an oil precipitates, which crystallizes at once. Filtration and drying is effected and threo-lp.nitrophenyl-Z-acetylamino-3-acetoxypropan-1-ol M. P. 162-163 C. is obtained.

Example 2 10 g. of erythro-l-p.nitrophenyl-2-amino-l,3-propanediol hydrochloride are suspended in a mixture of 10 cc. of saturated solution of hydrochloric acid in acetic acid plus 10 cc. of acetyl chloride. Stirring is efiected during 15 hours and then filtering-0E is eiiected from erythro- 1-p.nitrophenyl-1,3-diacetoXy-2-aminopropane hydrochloride M. P. 166469 C. formed.

13 g. of said hydrochloride are dissolved in cc. of water, cc. of acetone and then, at 0 C., 25 cc. of NaOH N/2 are added. After two hours, neutralization is effected at 0 C. with HCl N/ 1 and the acetone is distilled under vacuum.

By filtration, the erythro-1-p.nitrophenyl-Z-acetylamino- 1,3-propanediol M. P. 192 C. is obtained.

Example 3 10 g. of L-(+)-l-p.nitrophenyl-2-amino-1,3-propanediol are suspended in 24 cc. of saturated solution of hydrochloric acid in acetic acid (about 11%) and 16 cc. of acetyl chloride are added.

After one night, filtration is efiected from the L-(+)- 1-p.nitrophenyl-l,3-diacetoXy-2-aminopropane hydrochloride, which purified from methanol-ether has a M. P. 172 C. and (a) =+6.5 (methanol; c=4.18).

15 g. of said hydrochloride are dissolved in 60 cc. of water and further proceeding is effected as indicated in Example 1. The L-()-l-p.nitrophenyl-Z-acetylamino- 3-acetoxypropan-l-ol is obtained, which purified from ethyl acetate melts at l34136 C. with (a) =19.7 (methanol; c=3.86).

Example 4 10 g. of D-(-)-1-p.nitrophenyl-2-amino-1,3-propanediol hydrochloride are suspended in 10 cc. of dichloro- RCOCZI/ N07.C6H4.CH(O COR).CH(NH2.HC1).CH2O 0 OR NO2.CuH4.CHOH.CH(NH.C OR).CH:OH

aceticacid'and '10 cc. of 'dichloroacetyl chloride are added. After one night under agitation the mixture is cooled to 0 .C. Ice and an equal volume of acetone are added and the watery mixture thus obtained'is brought to pH 8'9with 10% sodium hydroxide. It is then left at a temperature of 0 C. 'for two hours. Then neutralization 'withHCl UN and distillation of the acetone under vacuum are effected.

'By filtration, the D-(+)-l-p.nitrophenyl-2-dichloroacetylamino-1,3-propanediol is collected, which re-crystallized from water melts at 149-l50 C. with (a) :+19 (ethanol; 'c-"-'5) We claim:

1. A' process for preparing acetylated derivatives of 1:p-nitrophenyl-Z-amino-l,3-propanediol, which comprises treating, under anhydrous conditions and at a temperature not higherthan 40 C., l-p-hitrophenyl-Z-aminol,3-pi'opanediol hydrochloride with a reactant saturated With gaseous hydrochloric acid and selected from the group consisting of acetyl chloride dissolved in acetic acid and dichl'oroacetyl chloride dissolved in dichloroacetic acid, separating 'the resulting l-p-nitrophenyl-1,3- diace'toxy-2-amino-propane hydrochloride, dissolving it in'water, adding an organic solvent miscible with water, adjusting the pH value to above 7 while keeping the temperature between 0 and 30 C., and separating the resulting crystalline product.

2. A process for preparing N,O-diacetylated derivatives of l-p-nitrophenyl-Z-amino-1,3-propanediol, which comprises treating, under anhydrous conditions and at a temperature not higher than 40 C., 1-p-nitrophenyl-2- amino*l-,3 -propanediol hydrochloride with a reactant saturated with gaseous hydrochloric acid and selected from the group consisting of acetyl chloride dissolved in acetic acid anddichloroacetyl chloride dissolved in dichloroacetic acid, separating the resulting 1-p-nitrophenyl-l,3-diacetoxy-Z-amino-propane hydrochloride, dissolving it in water, adjusting the pH value to between 7 and 8, and separating the resulting crystalline product.

3. A process according to claim 2, wherein the free base of 1-p-nitrophenyl-2-amino-l,3-propanediol is used insteadof t'he hydrochloride.

4. A process for preparing N-monoacetylated derivatives of l-p-nitrophenyl-Z-amino-1,3-propanediol, which comprises treating, under anhydrous conditions and at a temperature not higher than 40 C., 1-p-nitrophenyl-2- amino-1,3-propanediol hydrochlorid: with a reactant saturated'with gaseous hydrochloric acid and selected from the group consisting of acetyl chloride dissolved in acetic acid and dichloroacetyl chloride dissolved in =dichlomacetic acid, separating the resulting 1-p-nitrophenyl-1,3- diacetoxy-Z-aminopropane hydrochloride, dissolving it in water, adding an organic solvent miscible with water, adjusting the pH value to above 8 while'keeping the ternperature between 0 and 30C., and separating the resulting crystalline product. 7

5. A process according to claim 4, wherein the free base of l-p-nitrophenyl-Z-amino-1,3-propanediol is used instead of the hydrochloride. 7

6. A process for preparing threo-l-p-nitrophefiyl-Z- acetyl amino-3-acetoxypropane-1-ol, which comprises dissolving threo-l-p-nitrophenyl-2-amino-1,3-propanediol in glacial acetic acid, adding glacial acetic acid saturated with gaseous hydrochloric acid and acetyl chloride, permitting to stand for abouftwelve'hou'rs, diluting with ether, separating the resulting threo-1-p-nitropheny1-1,3- diacetoxy-Z-aminopropane hydrochloride, dissolving it in water, adjusting the pH value between Tend 8, and se'pa rating the oily precipitate which crystallizes at once.

7. A process for preparing D-(+)-1'-p-nitrophenyl-2 dichloroacetylamino-1,3-propanediol, which comprises suspending D- -1-p-nitrophenyl-2-amino-Lil-propanediol hydrochloride in dichloroacetic acid to which dichloroacetyl chloride has been added, agitating forabo'ut twelve hours, cooling to 0 C., adding ice and anequal volume of acetone, adjusting the pH value to between 8 and 9 with a 10% sodium hydroxide solution, neutralizing with 1N hydrochloric acid, removing acetone by vacuum distillation and separating the resulting crystalline product.

References Cited in the file of this patent UNITED STATES PATENTS 2,483,884 Crooks et al. 'Oct.'4, .1949 2,483,885 Crooks et al. Oct. 4, 1 949 2,538,764 Crooks et al. -Ian.'23, 1951 2,538,765 Crooks et al. Jan. 23, 1'95-1 OTHER REFERENCES Rebstock et al.: I. Am. Chem. Soc. vol. 71 (1949)., p.246l.

Controvlis et al.: J. Am. Chem. Soc. vol. 71 (1949.), p. 2468.

Phillips et al.: I. Am. Chem. Soc. vol. 72 1950), pp. 4920-21.

Phillips et al.: I. Am. Chem. Soc. vol- 69 (1947.), pp. 203-4. 

1. A PROCESS FOR PREPARING ACETYLATED DERIVATIVES OF 1-P-NITROPHENYL-2-AMINO-1,3-PROPANEDIOL, WHICH COMPRISES TREATING UNDER ANHYDROUS CONDITIONS AND AT A TEMPERATURE NOT HIGHER THAN 40* C., 1-P-NITROPHENYL-2-AMINO1,3-PROPANEDIOL HYDROCHLORIDE WITH A REACTANT SATURATED WITH GASEOUS HYDROCHLORIDE ACID AND SELECTED FROM THE GROUP CONSISTING OF ACETYL CHLORIDE DISSOLVED IN ACETIC ACID AND DICHLOROACETYL CHLORIDE DISSOLVED IN DICHLOROACETIC ACID, SEPARATING THE RESULTING 1-P-NITROPHENYL-1,3DIACETOXY-2-AMINO-PROPANE HYDROCHLORIDE, DISSOLVING IT IN WATER, ADDING AN ORGANIC SOLVENT MISCIBLE WITH WATER, ADJUSTING THE PH VALUE OF ABOUT 7 WHILE KEEPING THE TEMPERATURE BETWEEN 0 TO 30* C., AND SEPARATING THE RESULTING CRYSTALLINE PRODUCT.
 6. A PROCESS FOR PREPARING THREO-1-P-NITROPHENYL-2ACETYL AMINO-3-ACETOXYPROPANE-1-OL, WHICH COMPRISES DISSOLVING THREO-1-P-NITROPHENYL-2-AMINO-1,3-PROPANEDIOL IN GLACIAL ACETIC ACID, ADDING GLACIAL ACETIC ACID SATURATED WITH GASEOUS HYDROCHLORIDE ACID AND ACETYL CHLORIDE, PERMITTING TO STAND FOR ABOUT TWELVE HOURS, DILUTING WITH ETHER, SEPARATING THE RESULTING THREO-1-P-NITROPHENYL -1,3DIACETOXY-2-AMINOPROPANE HYDROCHLORIDE, DISSOLVING IT IN WATER, ADJUSTING THE PH VALUE BETWEEN 7 AND 8, AND SEPARATING THE OILY PRECIPITATE WHICH CRYSTALLIZES AT ONCE. 